Cellular thyroid hormone signalling mechanisms during weight maintenance
Endocrinology, Diabetology, Metabolism
Final Report Abstract
In the subproject TP3 of KFO 218 we tested the hypothesis, whether the thyroid hormone metabolite 3,5-T2, proposed to be generated in vivo from its precursor T3, the main thyromimetically active hormone, exerts beneficial effects in a high fat diet male mouse model. This model was established during the first funding period in close cooperation with TP 8c to mimic the human body weight MAINTAIN paradigm of the Z-Project after caloric reduction in combination with physical exercise. Furthermore, a novel chemiluminescence immunoassay, based on monoclonal antibodies raised in mice against 3,5-T2 BSA conjugates, has been established, validated and applied for determination of 3,5-T2 concentrations in human sera from various clinical studies. Uptake, metabolism and action of 3,5-T2 with respect to altered gene expression, biosynthesis of steroid hormones, drug metabolism, energy homeostasis and mitochondrial function was studied employing primary cultures of male mouse hepatocytes and the human hepatocarcinoma cell line HepG2. Unexpected adverse ‘side effects’ of 3,5-T2 on feedback regulation of the HPT axis and cardiac parameters were observed after application of the higher dose of 3,5-T2 to mice. This dose is needed to achieve the postulated ‘beneficial’ effects of this thyroid hormone metabolite, i.e. anti-steatotic hepatic action, improved serum lipid status and decreased body fat. A novel observation was that 3,5-T2 accumulates in liver, which has not been reported before for the classical thyroid hormones T4 and T3. This might explain its specific effects on hepatic cholesterol and sex steroid biosynthesis, again not observed after T3-administration in control mice. Ex vivo –omics analysis in mouse liver and mechanistic studies in hepatocyte models on the ‘beneficial’ hepatic anti-steatotic action indicate that 3,5-T2 appears to target also ‘classical’ nuclear TRβ receptors and thus exert T3-like action at concentrations required for its antisteatotic effects apart from the postulated direct, rapid mitochondrial action. Therefore, based on these observations in the high fat diet male mouse model, no recommendation can be made that 3,5-T2 might be a promising ‘slimming’ agent or useful as adjuvant in weight maintenance or reduction. Considering its suppression of the HPT axis as well as its effect on cardiac remodelling and weight increase in male mice, major concern should be expressed on its consumption in the wellness and body building scene. 3,5-T2 is widely used as pure drug or contained in several formulas and mixtures advertised for weight loss, melting of body fat or muscle building and available via the internet without prescription. Currently, commercially available assays used in clinical diagnostics of thyroid hormone status in healthy humans or patients will not detect this endogenously occurring or exogenously added biologically active thyroid hormone metabolite.
Publications
- (2014). "Detection of 3,5-diiodothyronine in sera of patients with altered thyroid status using a new monoclonal antibody based chemiluminescence immunoassay." Thyroid 24(9): 1350-1360
Lehmphul, I., et al.
(See online at https://doi.org/10.1089/thy.2013.0688) - (2015). "3,5-Diiodo-L-thyronine (3,5-T2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male dietinduced obese mice." Endocrinology 156(1): 389-399
Jonas, W., et al.
(See online at https://doi.org/10.1210/en.2014-1604) - (2016). "3,5-T2 alters expression of murine genes relevant for xenobiotic, steroid and thyroid hormone metabolism." J Mol Endocrinol 56(4): 311-323
Lietzow, J., et al.
(See online at https://doi.org/10.1530/JME-15-0159)
